SK287373B6 - The use of arylmethyl-carbonylamino-thiazole derivatives for the preparation of a pharmaceutical composition in the treatment of cell proliferative disorders - Google Patents

Abstract

2-amino-1,3-thiazole derivatives represented by formula (I) or (II) or pharmaceutically acceptable salts thereof are disclosed and the use of them for the preparation of a pharmaceutical composition in the treatment of cancer, cell proliferative disorders, Alzheimer's disease, viral infections, auto-immune diseases or neurodegenertive diseases.

Description

The present invention relates to the use of arylmethylcarbonylaminothiazole derivatives, in particular 2- (arylmethylcarbonylamino) -1,3-thiazoles for the manufacture of a medicament for the treatment of cancer and cell proliferative diseases.

BACKGROUND OF THE INVENTION

There are several cytotoxic drugs, e.g. fluorouracil (5-FU), doxorubicin and camptothecins, which damage DNA or affect cellular metabolic processes and thus, in many cases indirectly, disrupt the cell cycle. By inducing irreversible damage in both normal and tumor cells, these drugs have significant toxicity and side effects.

In this regard, it is highly desirable to develop highly specific antitumor agents that selectively lead to tumor cell damage and apoptosis, with the same efficacy as previously known antitumor drugs, but with reduced toxicity.

It is well known that the cycle of the cell cycle is controlled by a series of checkpoints, sometimes referred to as restriction points, that are regulated by a family of enzymes, the so-called. cyclin dependent kinases (cdk).

Cyclin-dependent kinases (cdk) are also regulated at many levels, e.g. binding to cyclins.

The normal cell cycle pathway is controlled by the coordination activation and inactivation of the various cyclin / cdk complexes. Both critical G1-S and G2-M transmissions are regulated by activation of various cyclin / cdk activities. In G1, cyclins D / cdk4 and cyclins E / cdk2 mediate the onset of the S-phase. The course of the S-phase requires cyclin A / cdk2 activity, whereas activation of cyclin A / cdk2 (cdk1) and cyclin B / cdc2 is required to trigger metaphases.

General information on cyclins and cyclin-dependent kinases is given e.g. in Kevin R. Webster et al., Exp. Opin. Invest. Drugs, 1998, vol. 7 (6): 865-887.

Control points in tumor cells are defective, partly due to poor regulation of cyclin-dependent kinase activity. For example, altered expression of cyclin E and cyclin-dependent kinases has been observed in tumor cells, and it has been shown that deletion of the KIP gene for the cdk inhibitor p27 in mice leads to a higher incidence of cancer.

These observations support the idea that cyclin-dependent kinases determine the rate of cell cycle pathway and are thus the target of chemotherapeutic intervention. In particular, direct inhibition of cyclin-dependent kinase / cyclin kinase activity could limit unregulated proliferation of tumor cells.

SUMMARY OF THE INVENTION

It is an object of the present invention to use a compound of formula (I) or (II) for the manufacture of a medicament for treating cell proliferative diseases related to altered cell-dependent kinase activity by administering to a mammal in need thereof an effective amount of a compound of formula (I) or (II). ).

(I) where

L is a phenyl or 5 to 6-membered aromatic heterocycle, with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R is (i) a C ₃ -C ₆ cycloalkyl group optionally substituted by a straight or branched C 1 -C ₆ alkyl group; or (ii) C | -C ₆ alkyl, straight or branched chain alkyl or arylalkyl group which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, C _r C ₆ alkyl, straight or branched alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, alkyl-C ₃ -C ₆ cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, aralkylcarbonylamino, arylaminosulfonyl, arylalkylaminosulfonylu, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, arylalk ylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-arylpiperazino, N-arylalkylpiperazino, piperidino and azabicyclo [3.2.2] nonane;

R ¹ is H or C _r C ₄ alkyl, straight or branched chain substituted with one or more hydroxy, alkoxy, amino, alkylamino or dilakylaminoskupinami;

R ² and R ³ , which may be the same or different, are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C ₆ alkyl group or an aryl group which may be optionally substituted as described for R 2; or

R ² and R ³ together with the nitrogen atom to which they are attached form 4-morpholinyl, 1-piperazinyl, N-alkylpiperazinyl, N-arylpiperazinyl, N-arylalkylpiperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring;

R ⁴ is a carboxy, a perfluorinated alkyl group, a C ₂ -C ₄ alkenyl group, a C ₂ -C ₄ alkynyl group, a 2-oxopyrrolidinyl group, a piperidinyl group or a straight or branched C 1 -C ₆ alkyl group, or an aryl group which is optionally substituted as described for R;

or a pharmaceutically acceptable salt thereof, provided that the compound is not

2- (4-aminophenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide,

2- (2-amino-l, 3-thiazol-4-yl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide,

2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide, N- (5-benzyl-1,3-thiazol-2-yl) -2 - [4- (dimethylamino) phenyl] acetamide, N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- (dimethylaminophenyl) acetamide or 2-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide.

In the claimed use, the compounds are useful in the treatment of cell proliferative diseases associated with altered cell-dependent kinase activity. These compounds have cdk / cyclin kinase inhibitory activity.

Furthermore, the compounds of the invention are useful in therapy as antitumor agents, but they are not toxic or cause side effects, which are disadvantages over the tumor agents discussed above.

The present inventors have found that 2-amino-1,3-thiazole derivatives have cdk / cyclin kinase inhibitory activity and are therefore useful in therapy as antitumor agents, but which are not toxic or cause side effects, which are disadvantages commonly available over tumor agents.

In particular, the compounds of the present invention have been found to be useful in the treatment of various cancers, including diseases such as: bladder, breast, intestine, kidney, lung cancer, including small lung cell cancer, esophagus, gall bladder, ovary, pancreas, stomach uterine throat, thyroid, prostate and skin, including squamous cell carcinoma; further for the treatment of hematopoietic tumors of the lymphoid lineage, such as leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hair cell lymphoma and Burkett's lymphoma; further for the treatment of hematopoietic tumors of the myeloid lineage, such as acute and chronic myelogenous leukemia, myelodysplastic syndrome, and promyelocytic leukemia; for the treatment of tumors of mesenchymal origin, including flbrosarcoma and rhabdomyosarcoma; for the treatment of tumors of the central and peripheral nervous system, such as astrocytoma, neuroblastoma, glioma and schwann; for the treatment of other tumors such as melanoma, seminoma, tetratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctantoma, thyroid follicular cancer, and Kaposi's sarcoma.

Due to the pivotal role of cyclin-dependent kinases in regulating cell proliferation, the present 2-amino-1,3-thiazole derivatives are useful for the treatment of many different cell proliferative disorders, such as benign prostatic hyperplasia, familial adenomatosis, polyposis, neuro-fibromatosis, psoriasis, atherosclerosis-related smooth muscle cell proliferation, pulmonary fibrosis, arthritis, glomerulonephritis and post-operative stenosis and restenosis.

The compounds of the present invention may be useful in the treatment of Alzheimer's disease, as evidenced by the fact that cdk5 is involved in tau protein phosphorylation (J. Biochem., 117, 741-749, 1995).

The present compounds, as modulators of apoptosis, may also be useful in the treatment of cancer, viral infections, in preventing the development of AIDS in HIV-positive persons, in the treatment of autoimmune and neurodegenerative diseases. The present compounds may be useful in inhibiting tumor angiogenesis and metastasis.

The present compounds may also act as inhibitors of other protein kinases, e.g. protein kinase C, her2, raf1, MEK1, MAP kinases, EGF receptor, PDGF receptor, IGF receptor, PI3 kinases, weel kinases, Src, Abl and thus become effective drugs for diseases related to other protein kinases.

According to a preferred embodiment of the invention, the cell proliferative disease is selected from the group consisting of cancer, Alzheimer's disease, viral infections, autoimmune diseases or neurodegenerative diseases. Specific cancers that can be treated include carcinoma, flat cell carcinoma, hematopoietic tumors of the myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central or peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratococtoma thyroid cancer and Kaposi's sarcoma.

According to another preferred embodiment of the described method, the cell proliferative disease is selected from the group consisting of benign prostatic hyperplasia, familial adematous polyposis, neuro-fibromatosis, psoriasis, atherosclerosis-related smooth muscle cell ploriferation, pulmonary fibrosis, arthritic glomerulonephritis and pooperative stenosis and postoperative stenosis.

Further, the method of the invention may provide inhibition of tumor angiogenesis and metastasis. The method of the invention also provides cell cycle inhibition and / or cdk / cyclin dependent inhibition.

The present invention provides 2-amino-1,3-thiazole represented by the general formula (I) or (II):

where

L is a phenyl group or a 5 to 6-membered aromatic heterocycle, with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

R is (i) a halogen atom, a nitro group, or both, or a group selected from pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-arylpiperazino, N-arylalkylpiperazino, piperidino and azabicyclo [3.2.2] nonane; or (ii) an amino group, optionally further substituted by one or more groups which may be the same or different and are selected from the group consisting of alkyl, aryl, arylalkyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, alkylcarbonyl, arylcarbonyl and arylalkylcarbonyl, wherein the alkyl moieties are optionally further substituted by one or more hydroxy or amino groups; or (iii) C ₃ -C ₆ cycloalkyl, optionally substituted C _r C ₆ alkyl group, straight or branched alkyl; or (iv) C _r C ₆ alkyl group, a linear or branched, or aryl group which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, C _r C ₆ alkyl, straight or branched alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, alkyl-C ₃ -C ₆ cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, aralkylcarbonylamino, arylaminosulfonyl, arylalkylaminosulfonyl, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, arylalkylaminocarbonyl, pyrrolidine o, morpholino, piperazino, N-alkylpiperazino, N-aryl-piperazino, N-arylalkylpiperazino, piperidino and azabicyclo [3.2.2] nonane; or (v) an aryl group which is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, straight or branched C 1 -C ₆ alkyl, arylthio, aryloxy , amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, alkyl-C ₃ -C ₆ cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl , alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, aralkylcarbonylamino, arylaminosulfonyl, arylalkylaminosulfonyl, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N -alkylpiperazino, N-aryl-piperazino, N-arylalkylpip erazino, piperidino and azabicyclo [3.2.2] nonane; or

R ¹ is H or C _r C ₄ alkyl, straight or branched chain substituted with one or more hydroxy, alkoxy, amino, alkylamino or dilakylaminovými groups;

R ² and R ³ , which may be the same or different, are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C ₆ alkyl group or an aryl group which may be optionally substituted as described for R 2; or

R ² and R ³ together with the carbon atom to which they are attached form 4-morpholinyl, 1-piperazinyl, N-alkylpiperazinyl, N-arylpiperazinyl, N-arylalkylpiperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3 azabicyclo [3.2.2] nonylovýkruh;

R ⁴ is a carboxy, a perfluorinated alkyl group, a C ₂ -C ₄ alkynyl group, a 2-oxopyrrolidinyl group, a piperidinyl group or a straight or branched C 1 -C ₆ alkyl group, or an aryl group which is optionally substituted as described for R; or a pharmaceutically acceptable salt thereof.

The present invention also provides a process for preparing a 2-amino-1,3-thiazole described derivative, or a pharmaceutically acceptable salt thereof, by reacting a compound of formula (III)

with the compound represented by the general formula (IV):

where

R, L, R ¹ , R ² and R ³ are as defined above,

Z is hydroxy or a suitable leaving group for the preparation of the 2-amino-1,3-thiazole derivative represented by the general formula (I), wherein R, L, R ¹ , R ² and R ³ are as defined above.

The present invention also provides a process for preparing the described 2-amino-1,3-thiazole derivative or a pharmaceutically acceptable salt thereof by reacting a compound represented by the general formula (I):

with the compound represented by the general formula (V):

R ₄ COX (V), where

R, R ¹ , L and R ⁴ are as defined above and

X is hydroxy or a suitable leaving group such as chloro or bromo to give the 2-amino-1,3-thiazole derivative represented by the general formula (II), wherein R, L, R ¹ and R ⁴ are as defined above.

The present invention also provides a process for preparing the described 2-amino-1,3-thiazole derivative or a pharmaceutically acceptable salt thereof, by reacting the 2-amino-1,3-thiazole derivative represented by the general formula (I), wherein both or at least one of R ² and R ³ is a hydrogen atom, with a compound represented by the general formula (VI):

R’-Y (VI) where

R 1 is as defined for R ² or R ³ , but is other than hydrogen, and

Y is a suitable leaving group, to form a 2-amino-1,3-thiazole derivative of formula (I) wherein both or at least one of R ² or R ³ is other than hydrogen; and optionally converting the 2-amino-1,3-thiazole derivative represented by the general formula (1) or (II) to another 2-amino-1,3-thiazole derivative represented by the general formula (I) or (II) and / or its salt.

The present invention also provides a pharmaceutical composition comprising the described 2-amino-1,3-thiazole derivative and at least one pharmaceutically acceptable carrier and / or diluent.

A full understanding of the present invention and many other advantages will be apparent from the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Some 2-amino-1,3-thiazoles are known as herbicides, synthetic intermediates or even as therapeutic agents. Of these, for example, 2-benzamido-1,3-thiazoles are known antiallergic agents (EP-A-261 503, Valeas S.P.A.); 5-alkyl-2-phenylalkylcarbonylamino-1,3-thiazoles are known as protein kinase C inhibitors (WO 98/04536, Otsuka Pharmaceutical Co); 5-arylthio-2-acylamino-1,3-thiazoles are known as anticancer agents (EP-A-412 404, Fujisava Pharm. Co); 4-amino-2-carbonylamino-1,3-thiazoles are known as cyclin-dependent kinase inhibitors (WO 99/21845, Agouron Pharmaceuticals Inc.).

Unless otherwise indicated, the term halogen means a fluorine, chlorine, bromine or iodine atom.

Unless otherwise indicated, the term alkyl, alkoxy, and _R is C _C6 alkyl or C _r C ₆ alkoxy.

The term straight or branched is C _r C ₆ alkyl or C _r C ₆ alkoxy group selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl , n-hexyl, methoxy, ethoxy, n-propxy, isopropxy, n-butoxy and the like.

Similarly, the term N-alkylpiperazinyl, alkylsulfonyl, alkylcarbonyl, alkylthio, dialkylamino, alkoxyamino, arylakyl, alkylamino, alkylcycloalkyl, alkoxycarbonyl, alkoxycarbonylamino and the like include those groups wherein alkyl and alkoxy moieties have C 1 -C ₆ alkyl or alkoxy groups.

Unless otherwise indicated, the term cycloalkyl is C ₃ -C _f, a cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl as well as cycloalkyl and bridged cycloalkyl groups with up to 10 carbon atoms, for example, an adamantane group.

The term aryl includes mono-, bi- or polycarbocyclic hydrocarbons having 1 to 4 ring moieties, wherein at least one ring moiety is aromatic, which are either fused or bonded together by single bonds. These groups may contain 5 to 20 carbon atoms, preferably 6 to 20 carbon atoms.

The term heterocycle includes heteroaromatic rings, including 5 or 6-membered saturated or unsaturated carbocycles, wherein one or more carbon atoms are replaced by one or more atoms selected from nitrogen, oxygen and sulfur.

Examples of aryl groups are phenyl, 1-naphthyl, 2-naphthyl, indanyl, indenyl, biphenyl, benzocyclolalkyl, e.g. bicyclo [4.2.0] octa-1,3,5-triene, benzoheterocyclyl, e.g. benzodioxolyl, quinoxalyl, indolyl, optionally benzocondensed pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl and the like.

The term C ₂ -C ₄ alkenyl or alkynyl includes groups selected from the group consisting of vinyl, allyl, 1-propenyl, isopropenyl, 1-butanol, 2-butenyl, 3-butenyl, ethynyl, propynyl, butynyl and the like.

The term perfluorinated alkyl and alkoxy refers C _r C ₄ alkyl or alkoxy, substituted by one or more fluoro atoms, for example trifluoromethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, trifluoromethoxy and the like .

Pharmaceutically acceptable salts of the compounds of formula (I) or (II) include acid addition salts with inorganic or organic acids such as nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, lactic, oxalic, malonic , apple, wine, lemon, benzoic, cinnamon, almond, methanesulfonic, isethionic and salicylic, as well as salts with inorganic or organic bases such as alkali or alkaline earth metals, in particular sodium, potassium, calcium or magnesium hydroxides, carbonates or bicarbonates , acyclic or cyclic amines, in particular methylamine, ethylamine, diethylamine, triethylamine and piperidine.

The compounds of formula (I) or (II) may contain asymmetric carbon atoms and may therefore exist either in the form of racemic mixtures or as individual optical isomers.

Accordingly, the use of the compounds of formulas (I) and (II) and all possible isomers and mixtures and metabolites thereof and pharmaceutically acceptable bio-precursors (other than those referred to as prodrugs) as an anticancer agent is within the scope of the present invention.

Preferred compounds of the invention of formula (I) or (II) are those wherein L is phenyl, thiazole, imidazole, oxazole, pyrazole, isoxazole, thiophene, pyridine or pyrimidine; R is (i) a halogen atom, (ii) a group selected from arylamino, alkylamino or dialkylamino, wherein the alkyl moiety may be further substituted with one or more hydroxy or amino groups, (iii) a C ₃ -C ₆ cycloalkyl group optionally substituted with an alkyl group , (iv) cards or branched C _r C ₄ alkyl or aryl coatings group each optionally substituted as above, (b) optionally substituted aryl; R ¹ is H or C _r C ₄ alkyl optionally substituted with hydroxy or amino.

Even more preferred compounds of this class are compounds of formula (I) or (II) wherein L is phenyl or thiazole; R is selected from the group consisting of alkylamino or dialkylamino, wherein the alkyl may be further substituted with one or more hydroxy or amino groups, C ₃ -C _(cycloalkyl, straight or branched C _r C ₄ alkyl optionally substituted with one or more hydroxy, amino, alkylamino, dialkylamino, pyrrolidino, morpholino, N-alkylpiperazino, azabicyclo [3.2.2] nonane; R ¹ is hydrogen; R ² and R ³ are the same or different and are hydrogen, adamantyl, straight or branched C 1 -C 6 alkyl optionally substituted with one or a plurality of groups selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, morpholino, N-alkylpiperazino, imidazole, 3-azabicyclo [3.2.2] nonane, aminocarbonyl, dialkylaminocarbonyl; to which they are bound, R ² and R ³ form a 4-morpholinyl, N-alkylpiperazinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring, and R ⁴ is carboxy, perfluorinated alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, 2-oxopyrrolidinyl, piperidinyl, aryl, optionally substituted with a substituent selected from the group consisting of halogen, dialkylamino, aminosulfonyl, aminocarbonyl, alkoxy, hydroxy, alkylcarbonylamino, amino, pyrrolidino N-alkylpiperazino, morpholino; and R ⁴ is straight or branched C _r C ₆ alkyl group optionally substituted by a radical from the group consisting of halogen, hydroxy, alkoxy, alkylthio, arylthio, C ₃ -C ₆ cycloalkyl, cyano, carboxy, amino, alkylamino, dialkylamino, pyrrolidino, morpholino, N-alkylpiperazino, azabicyclo [3.2.2] nonane, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aryl, optionally substituted with a substituent selected from the group consisting of halogen, dialkylamino, aminosulfonyl, aminocarbonyl, alkoxy, hydroxy, alkylcarbonylamino, amino, , pyrrolidino, N-alkylpiperazino or morpholino.

Examples of preferred compounds of formula (I) or (II) of the invention, which may be in the form of pharmaceutically acceptable addition salts, for example bromides or chlorides, include the following: N- (4- {2 - [(5-isopropyl-1,3) -thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acrylamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2-methylpropanamide; 2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2-naphthamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) benzamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2-phenyl-acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (3-pyridyl) acetamide;

2,2,3,3,3-pentafluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) propanamide, 2 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino -2-oxoacetic acid; 2-Fluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; 2-chloro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide; 2-cyano-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-oxo-betaalanine; N'1 '- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malonamide;

4 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-oxobutyric acid ;

2- [2- (glycoloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;

3-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide;

3-amino-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; 2-Amino-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide;

4-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide;

4-amino-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) butanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (4-methyl- piperazinyl) acetamide; 2- (4-Benzyl-1-piperazinyl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) acetamide;

N- (4- (2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1-piperidinyl) acetamide: N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide;

2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2 yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl) -1,3-thiazol-2-yl) -2- (1H-1, 3-thiazol-2-yl) amino] 2,3,4-tetraazol-1-yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2-pyrrolidinecarboxamide; N '- (4) - {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinamide;

3- (1H-benzimidazol-2-yl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) propanamide;

-acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide; 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;

4-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-methoxyacetamide;

3.3.3-Trifluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide ; 2- (dimethylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2 - {[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thiazol-4-yl ) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2- {methyl [2- (4-methyl-l-piperazinyl) ethyl] amino} -l, 3-thiazol-4- yl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2 - {[2- (4-morpholinyl) ethyl] amino} -1,3'-thiazol-4-yl) acetamide ; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl)] amino} -1,3-thiazol-4-yl) acetamide ; 2- {2 - [(2,3-dihydroxypropyl) amino] 3-thiazol-4-yl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- {2 - [(2,3-dihydroxypropyl) (methyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- (2 - {[3- (dimethylamino) -2-hydroxypropyl] amino} -l, 3-thiazol-4-yl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- {2 - [(2-amino-2-oxoethyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- (2 - {[2- (dimethylamino) -2-oxoethyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- [2- (adamantylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-methyl-l-piperazinyl) phenyl] acetamide;

N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (l-pyrrolidinyl) phenyl] acetamide;

N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4 - {[2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4- {methyl [2- (4-methyl-l-piperazinyl) ethyl] amino} phenyl) acetamide;

N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4 - {[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide;

2- {4 - [(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- {4 - [(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- (4 - {[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- [4- (l-adamantylamino) phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- {4 - [(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- (4 - {[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- [4- (acetylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-thiophene-2-carboxamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-pyrazine-2-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-isoxazole-4-carboxamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isoxazolecarboxamide; (Dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;

4- (acetylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 4- (dimethylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -l, 3-benzodioxole-5-carboxamide; 4- (aminosulfonyl) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 2-chloro-2,2-difluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide;

2-cyano-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide;

-acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide;

N '- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxyacetamide;

3.3.3-trifluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenyl-acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenyl-acetamide;

2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide N- (4 - {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl) -2H-1,2 , 3,4-tetraaza-2-yl] acetamide;

2-Cyclopropyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -5-methyl-2-pyrazinecarboxamide ; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-propynamid;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl-1,3 -oxazole-4-carboxylic acid amide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3-dimethylbutanamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -3-methyl-2-butenamide ;

3-Cyclopentyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (3-thienyl) -acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) acetamide;

2,2,2-trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -3- (2-thienyl) propanamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -l-oxoethyl}, 3-thiazol-2-yl) - (4-pyridyl-thio) acetamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (3-pyridyl) -l, 3-thiazole-4-carboxylic acid amide;

2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- (5-cyclopropyl-l, 3-thiazol-2-yl) acetamide;

2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- {5 - [(3-hydroxypropyl) (methyl) amino] thiazol-3-yl) acetamide;

2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5 - [(2-hydroxyethyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide;

2- [4- (dimethylamino) phenyl] -N- {5 - [(2-hydroxyethyl) (methyl) amino] -l, 3-thiazol-2-yl} acetamide;

2- [4- (dimethylamino) phenyl] -N- {5 - [(3-hydroxypropyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide and N- (5-cyclopropyl-1,3) -thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide.

Compounds of formula (I) or (II) may be prepared, for example, by a process comprising (a) reacting a compound of formula (III):

NH 3 (III) with a compound of formula (IV):

(IV), wherein R, L, R ¹ , R ² and R ³ are as defined above and Z is hydroxy or a suitable leaving group, to give a compound of formula (I) wherein R, L, R ¹ , R ² and R ³ are as defined above;

or (b) reacting a compound of formula (I)

with a compound of formula (V):

R 4 -COX (V) wherein R, R ¹ , L and R ⁴ are as defined above and X is hydroxy or a suitable leaving group such as chlorine or bromine to give a compound of formula (II) wherein R, R ¹ , L and R ⁴ are as defined above; or (c) reacting a compound of formula (I) wherein both or at least one of R ² and R ³ is hydrogen with a compound of formula (VI):

R'-Y (VI) wherein R 'has the meanings of R ² or R ³ but other than hydrogen and Y is a leaving group such as bromine, chlorine, mesyl, tosyl, hydroxyl or formyl (CHO) to give a compound of formula (I) wherein both or at least one of R ² and R ³ is other than hydrogen; and optionally converting a compound of formula (I) or (II) to another compound of formula (I) or (II) and / or a salt thereof.

One skilled in the art is aware that when a compound of formula (I) or (II) of the invention is prepared according to the above process in the form of a mixture of isomers, then the separation of such a mixture into the individual isomers by conventional methods is within the scope of the present invention. Similarly, the conversion of the corresponding salts to the free compounds of formula (I) or (II) according to known procedures is within the scope of the present invention.

Said processes (a), (b) or (c) may be carried out according to procedures known in the art.

Reaction of a compound of formula (III) with a compound of formula (IV) wherein Z is a hydroxy group according to process (a) or a compound of formula (I) wherein R ² and R ³ are both hydrogen with a carboxylic acid of formula V ), wherein X is hydroxy, according to process (b) may be carried out in the presence of a coupling agent such as carbodiimide, ie 1,3-dicyclohexylcarbodiimide,

1,3-diisopropylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or using a polymer-supported carbodiimide such as N-cyclohexylcarbodiimide, N'-methyl polystyrene in a suitable solvent such as dichloromethane, chloroform, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, toluene or Ν, Ν-dimethylformamide at a temperature ranging from -10 ° C to reflux temperature, for a suitable period of time, for example in the range of about 30 minutes to about 8 days.

Reaction between a compound of formula (III) and a compound of formula (IV) wherein Z is hydroxy or between a compound of formula (I) wherein R ² and R ³ are hydrogen with a compound of formula (V) wherein X is hydroxy , can also be carried out, for example, by the anhydride mixture method, using a chloroformate such as ethyl, isobutyl or isopropyl chloroformate in the presence of a tertiary base such as triethylamine, Ν, di-diisopropylethylamine and pyridine in a suitable solvent such as toluene, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, diethyl ether, 1,4-dioxane or N, N-dimethylformamide, at about -30 ° C to room temperature.

The reaction between a compound of formula (III) and a carboxylic acid derivative of formula (IV) wherein Z is a suitable leaving group according to process (a) or between a compound of formula (I) wherein both R ² and R ³ are hydrogen and a carboxylic acid derivative of formula (V) wherein X is a suitable leaving group according to process (b) may be carried out in the presence of a tertiary base such as triethylamine, Ν, Ν-diisopropylethylamine or pyridine in a suitable solvent such as toluene, dichloromethane, chloroform, diethyl ether, tetrahydrofuran, acetonitrile or Ν, Ν-dimethylformamide at a temperature ranging from -10 ° C to reflux.

The reaction between a compound of formula (I) and a compound of formula (VI) wherein Y is a suitable leaving group, according to process (c), may be carried out in the presence of a suitable base such as potassium carbonate, triethylamine, Ν, Ν-diisopropylethylamine or pyridine, in a suitable solvent such as ethanol, acetonitrile, Ν, Ν-dimethylformamide, 1,4-dioxane or tetrahydrofuran, at a temperature from room temperature to the reflux temperature.

The reaction between a compound of formula (I) and a compound of formula (VI) wherein Y is hydroxy, according to process (c), may be carried out under Mitsunobu conditions, in the presence of triphenylphosphine and diethyl azodicarboxylate, in a suitable solvent such as tetrahydrofuran. 0 ° C to room temperature.

The reaction between a compound of formula (I) and a compound of formula (VI) wherein Y is CHO according to process (c) can be carried out in the presence of conventional reducing agents such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride in a suitable solvent such as methanol or ethanol at a temperature of from 0 ° C to the reflux temperature.

Also, the optional conversion of a compound of formula (I) or (II) to another compound of formula (I) or (II) may be carried out according to known methods.

For example, process (c) may be considered as a possible conversion of a compound of the invention to another compound of the invention.

Optionally converting to a salt of a compound of formula (I) or (II) or converting a salt to a free compound, as well as separating the mixture of isomers into the individual isomers can be accomplished by conventional methods.

The compounds of formula (III), (IV), (V) and (VI) according to the invention are known compounds or can be obtained according to known procedures.

A compound of formula (IV) or (V) wherein Z is X or a leaving group as defined can be obtained according to conventional methods of the corresponding carboxylic acid of formula (IV) or (V), wherein Z is hydroxy.

A compound of formula (III) wherein R is as defined above may be prepared, for example, by reacting a compound of formula (VII):

W

Wherein R is as defined above and W is a bromine or chlorine atom, with thiourea, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, 1,4-dioxane or toluene, at a temperature between room temperature and reflux temperature, a suitable time, ranging from 1 hour to 24 hours.

Compounds of formulas (IV) to (VII) are in some cases commercially available products or can be prepared by methods known in the art.

In the preparation of the compounds of formula (I) according to the invention, optional functional groups must be protected by conventional techniques, both in the starting materials and in the intermediates which could undergo undesired reactions.

Similarly, the conversion of the latter to the free unprotected compounds can be carried out according to known methods.

pharmacology

Compounds of formula (I) or (II) are active as cdk / cyclin inhibitors, giving positive results in tests performed according to the procedures described below.

The inhibitory activity of the putative cdk / cyclin inhibitors and the efficacy of the selected compounds were determined using MultiScreen-PH 96 well plates (Millipore) in which a phosphocellulose filter paper was placed at the bottom of each well allowing binding of the positively charged substrate after the washing / filtration step.

Once the radiolabeled phosphate group was transferred by ser / threo kinase to filter-bound histone, the emitted radiation was measured by a scintillation counter.

The cdk2 / cyclin A activity inhibition assay was performed as follows:

Kinase reaction: 1.5 M histone H1 substrate, 25 M ATP (0.5 gCiP33g-ATP), 100 ng cyclin A / cdk2 complex, 10 M inhibitor in a final volume of 100 μΐ buffer (TRIS HCl 10 mM, pH 7.5 (MgCl ₂ 10 mM, 7.5 mM DTT) are added to each of the 96 wells. After 10 min. Incubation at 37 ° C is stopped by adding 20 μΐ of EDTA 120 mM.

Capture: 100 μΐ was transferred from a MultiScreen plate from each well to allow the substrate to bind to a phosphocellulose filter. Plates were washed 3 x 150 μΐ / well with PBS containing no Ca ⁺⁺ / Mg ⁺⁺ and filtered through a MultiScreen filtration system.

Detection: filters were dried at 37 ° C, scintillation solution was added, 100 μΐ / well, and ³³ P-labeled histone H1 was detected by Top-Count radioactivity assay.

Results: data were analyzed and expressed as% inhibition relative to total enzyme activity (= 100%).

All compounds having an inhibition greater than 50% were further studied and the Ki inhibition profile was calculated.

The procedure used was identical to that described except for the concentration of ATP and substrate. The concentrations of ATP and histone H1 substrate were varied: 4, 8, 12, 24, 48 AM for ATP (containing proportionally diluted P33g-ATP) and 0.4, 0.8, 1.2, 2.4, 4.8 AM for histone were used in the absence or presence of two different, carefully selected concentrations of inhibitors.

Experimental data were analyzed by computer program SigmaPlot and determined Ki values using random bireactive equation system:

Vmax (A) (B) and KBKB

IN - ----------____________________

1+ <A) + (A) + (A) (A)

KAKB aKAKB

Where A = ATP and B = histone H1

By way of example, the activity of the compound of the invention 2- [2- (acetylamino) 1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide [0,5 ( M)].

In addition, the activity of the cdk / cyclin complex inhibitor and the potency of the selected compounds were determined by the SPA (Scintilation Proximity Assay) on 96-well assay plates. This assay is based on the ability of streptavidin coated SPA beads to capture a biotinylated peptide derived from the histone phosphorylation site.

Once the radiolabeled phosphate moiety is converted by a ser / threo kinase to a biotinylated histone peptide, the scintillation counter measures the emitted radiation.

The cdk5 / p25 activity inhibition assay was performed as follows:

Kinase reaction: 1.0 M biotinylated histone peptide substrate, 0.25 P33g-ATP, 4 nM cdk2 / p25 complex, 0-100 M inhibitor in a final volume of 100 μΐ buffer (Hepes 20 mM pH 7.5, MgCl ₂ 15 mM , 1 mM DTT) is added to the bottom of each well of the plate. After a 20 minute incubation at 37 ° C, the reaction was stopped by adding 500 µg of SPA beads in phosphate buffered saline containing 0.1% Triton X-100, 50 µΜ ATP and mM EDTA. The beads were decanted and the radioactivity incorporated in the ³³ P-labeled peptide was determined on a Top count scintillation counter.

Results: Data were analyzed and expressed as% inhibition according to the formula:

100X (l - (unknown-Bkgd) (Enz. Control-Bkgd).

IC 50 values were calculated using variations of the four parameters of the logistic equation:

Y = 100 / [1 + 10 ^A ((LogEC50-X) * slope), where X = log (gM) and Y =% inhibition).

The compounds of formula (I) or (II) can therefore be used to limit the unregulated proliferation of tumor cells and thus in the treatment of various cancers, such as carcinomas, e.g. breast, lung, bladder, colon, endometrial and ovarian tumors, sarcomas such as soft vessel sarcomas or bone sarcomas, and hematologic malignancies such as leukemia.

The compounds of formula (I) and (II) are also useful for the treatment of other cell proliferative diseases such as psoriasis, atherosclerosis-related smooth muscle cell proliferation and post-operative stenosis and restenosis, and Alzheimer's disease.

Compounds of formula (I) or (II) of the present invention suitable for administration to mammals, for example humans, may be administered by conventional routes and dosage levels depend on the age, weight, condition of the patient and route of administration.

For example, a suitable oral dose of a compound of Formula (I) or (II) may range from about 10 to about 500 mg per dose and may be administered 1 to 5 times daily.

The compounds of the present invention may be administered alone or alternatively, in combination with known anticancer therapies, such as radiation therapy or chemotherapy, in combination with known cytostatic or cytotoxic agents, antibiotics, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon agents type, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), metallomatric protease inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptors, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents, inhibitors of famesyltransferase, signal transduction inhibitors , cell cycle inhibitors, other cdk inhibitors, tubulin binding agents, topoisomerase yl inhibitors, topoisomerase II inhibitors and the like.

By way of example, the compounds of the invention may be administered in combination with one or more chemotherapeutic agents such as taxane, taxane derivatives, encapsulated taxanes, CPT-11, camphothecin derivatives, anthracycline glycosides such as doxorubicin, idarubicin, epirubicin, etoposide, navelbine, vinblastine, carboplatin, cisplatin, etramustine, celecoxib, Sugen SU-5416, Sugen SU-6668, Herceptin and the like, optionally in the form of a liposomal formulation.

When in the form of a fixed dose, such combination products comprise a compound of the invention in the dosage range described above and an additional pharmaceutically active agent within the approved dosage range.

Compounds of formula (I) may be used sequentially with known anticancer agents if combination therapy is inappropriate.

The compounds of the invention may be administered in various dosage forms, for example orally in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, for example, intramuscularly or intravenously, and / or intrathecally, and / or intraspinally by injection or infusion.

The present invention also encompasses pharmaceutical compositions comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient (which may be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared by conventional means and are administered in a pharmaceutically acceptable form.

For example, solid oral dosage forms may contain, together with the active compound, diluents such as lactose, dextrose, sucrose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binders such as starch, acacia, gelatin, methylcellulose, carboxymethylcellulose or polyvinylpyrrolidone; disaggregating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescent mixtures; coloring agents; sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulfates; and general, non-toxic, pharmacologically inactive substances used in pharmaceutical formulations. These pharmaceutical compositions are processed by known methods, for example, by mixing, granulating, tabletting, sugar-coated or film-coated. Liquid dispersions for oral administration may be, for example, syrups, emulsions or suspensions.

Syrups may contain as carrier, for example, sucrose or sucrose with glycerin and / or mannitol, and / or sorbitol.

The suspensions and emulsions may contain as carrier, for example, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, for example sterile water, olive oil, ethyl oleate, glycols, for example propylene glycol and, if desired, an appropriate amount of lidocaine hydrochloride. Solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or preferably are in the form of sterile aqueous isotonic saline or may contain as carrier propylene glycol.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, for example, cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant, or lecithin.

The following examples illustrate the present invention but do not limit its scope.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided to illustrate the present invention but are not intended to limit the scope of the invention in any way.

Example 1

Preparation of 2-amino-5-isopropyl-1,3-thiazole 3-methylbutyraldehyde (18.6 mmol) was dissolved in 1,4-dioxane (15 ml). 40.4 ml (18.6 mmol) of a 2% v / v solution of bromine in 1,4-dioxane are then added dropwise at 0 ° C. The mixture was kept at room temperature with stirring for 2 hours and then 2.83 g (37.2 mmol) of thiourea and 5 ml of ethanol were added.

After 6 h at room temperature the solution was evaporated to dryness, the residue was dissolved in CH ₂ C1 ₂ and the product was extracted with IM hydrochloric acid; the aqueous layer was made basic using 30% NaOH solution and extracted with CH ₂ C1 _2nd The organic phase is dried over sodium sulfate. The residue is chromatographed on silica gel, eluting with mixtures of cyclohexane and ethyl acetate to give 1.1 g (42% yield) of the title compound.

1 H-NMR (DMSO-d 6) ppm: 6.6 (s, 2H, NH ₂ ); 6.58 (s, 1H, thiazole CH); 2.9 (m, 1H, CHMe ₂ ); 1.18 (s, 3H, MeCHMe); 1.17 (s, 3H, MeCHMe).

Analogously starting from the corresponding aldehyde, the following product can be prepared: 2-amino-5-cyclopropyl-1,3-thiazole.

Example 2

Preparation of tert-butyl 4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-ylcarbamate

EDCI (20.6 g, 107 mmol) was added to a solution of 2- {2 - [(tert-butoxycarbonyl) amino] -1,3-thiazol-4-yl} acetic acid (25 g, 97 mmol) under ice-cooling. in CHCl ₃ (200 mL).

After stirring for 1 h, a solution of 2-amino-5-isopropyl-1,3-thiazole (13.7 g, 97 mmol) in CHCl ₃ (150 mL) was added and the mixture was maintained at 0 ° C for 1 h and then at room temperature overnight.

The resulting solution was washed with water, 5% citric acid, saturated sodium bicarbonate solution and brine.

After drying over sodium sulfate and evaporation, a solid is obtained which is chromatographed on silica gel using CH ₂ Cl ₂ : MeOH 95: 5 as eluent to give the title compound as a colorless solid (22 g; 59%)

1.1. 196-197 ° C (1 H-NMR DMSO-d 6) ppm: 12 (s, br, 1H, NH); 11.4 (s, br, 1 H, NHBoc); 7.14 (s, 1H, H 4 -thiazole); 6.9 (s, 1H, H5-thiazole); 3.7 (s, 2H, _CH2); 3.08 (m, 1H, CHMe ₂ ); 1.42 (s, 9H, t-Bu); 1.22 (d, 6H, CHMe ₂ ).

Analogously starting from the corresponding carboxylic acid, the following product can be prepared: tert-butyl 4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenylcarbamate

1.1. 179-180 ° C 1 H-NMR (DMSO-d 6 ppm: 12.1 (s, br, 1H, NH); 9.22 (s, br, 1H, NHBoc); 7.35 (d, 2H, Ph) 7.19 (s, 1H, H 4 -thiazole); 7.15 (d, 2H, Ph); 3.6 (s, 2H, CH ₂ ) CHMe ₂ ); 1.43 (s, 9H, t-Bu); 1.11 (d, 6H, CHMe ₂ ).

Example 3

Preparation of 2 - (- amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide

Trifluoroacetic acid (168 mL) was added to a solution of tert-butyl 4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl) -1,3-thiazole- 2-ylcarbamate (22 g, 57.51 mmol) in CH ₂ C1 ₂ (750 ml) and anisole (9.33 ml, 86.27 mmol).

The mixture was stirred at 0 ° C for 2 hours, the solution was kept at room temperature overnight and then evaporated. The residue was dissolved in CH ₂ C1 ₂ and evaporated (500 ml x 3).

The residue was partitioned between CH ₂ C1 ₂ and water. The organic layer was further washed with water, saturated sodium bicarbonate, and brine.

Then the mixture is dried over sodium sulfate and evaporated to give a solid which is triturated with isopropylcyclohexane to give the title compound as a beige solid (13 g; 81%), m.p. Mp 201-203 ° C.

1 H-NMR (DMSO-d 6) ppm: 11.98 (s, br, 1H, NH); 7.13 (s, br, 1H, NHBoc); 7-6.6 (m, 4, Ph); 5.9 (s, br, 2H, NH _2); 3.55 (s, 2H, _CH2); 3.08 (m, 1H, CHMe ₂ ); 1.12 (d, 6H, CHMe ₂ ).

The following product can be prepared analogously: 2- (4-aminophenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide

1.1. 165-166 ° C 1 H-NMR (DMSO-d 6) ppm: 11.98 (s, br, 1H, NH); 7.13 (s, 1H, H 4 -thiazole); 7-6.6 (m, 4H, Ph); 5.9 (s, br, 2H, NH _2); 3.55 (s, 2H, _CH2); 3.08 (m, 1H, CHMe ₂ ); 1.12 (d, 6H, CHMe ₂ ); 4-amino-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) butanamide;

3-amino-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; and

2-amino-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide.

Example 4

Preparation of 2-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide

EDCI (0.49 g, 2.54 mmol) was added to a solution of 2-chloroacetic acid (0.24 g, 2.54 mmol) in CHCl 3 (10 mL) under ice-cooling.

The mixture was stirred at 0 ° C for 1 hour, a solution of 2- (2-amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) was added dropwise. of acetamide (0.6 g, 2.12 mmol) in CHCl ₃ (10 mL) and the reaction mixture was maintained at 0 ° C for 1 hour and then at room temperature overnight.

The solution was washed with water, 5% citric acid, water, saturated sodium bicarbonate solution and brine.

Drying over sodium sulfate and evaporation gave a solid which was chromatographed on silica gel using CH ₂ Cl ₂ then CH ₂ Cl ₂ : MeOH 99: 1 as eluent to give the title compound as a colorless solid (0.49 g; 65%).

1.1. 176-178 ° C 1 H-NMR (CDCl 3) ppm: 11 (s, br, 2H, 2NH); 7.01 (s, 1H, H 4 -thiazole); 6.83 (s, 1H, H5-thiazole); 4.23 (s, 2H, CH ₂ C1); 3.83 (s, 2H, _CH2 CO); 3.1 (m, 1H, CHMe ₂ ); 1.35 (d, 6H, CHMe ₂ ).

The following products can be prepared analogously:

2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide

1.1. 174-176 ° C 1 H-NMR (DMSO-d ₆ ) ppm: 12.1 (2s, br, 2H, 2NH); 7.15 (s, 1H, H 4 -thiazole); 6.93 (s, 1H, H5-thiazole); 3.77 (s, 2H, _CH2); 3.3 (s, 3H, CH ₃ ); 3.1 (m, 1H, CHMe ₂ ); 1.22 (d, 6H, CHMe ₂ );

4-Chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide

1.1. 170-172 ° C 1 H-NMR (DMSO-d 6) ppm: 12.15 (s, br, 1H, NH); 12.05 (s, br, 1 H, NH); 7.12 (s, 1H, H 4 -thiazole); 6.95 (s, 1H, H5-thiazole); 3.76 (s, 2H, _CH2 CO); 3.62 (t, 2H, CH ₂ CH ₂ CH ₂ C 1); 3.08 (m, 1H, CHMe ₂ ); 2.55 (t, 2H, CH ₂ CH ₂ CH ₂ CH ₂ C 1); 2 (tt, 2H, CH ₂ CH ₂ CH ₂ C 1); 1.1 (d, 6H, CHMe ₂ );

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2-methoxy-acetamide

1.1. 147-149 ° C 1 H-NMR (DMSO-d 6) ppm: 12.03 (s, br, 1H, NH); 7.11 (s, 1H, H 4 -thiazole); 6.98 (s, 1H, H5-thiazole); 4.09 (s, 3H, OMe); 3.79 (s, 2H, _CH2); 3.1 (m, 1H, CHMe ₂ ); 1.2130 (d, 6H, CHMe ₂ );

3,3,3-Trifluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide

1.1. 214-216 ° C 1 H-NMR (DMSO-d 6) ppm: 12.5 (s, br, 1H, NH); 12.1 (s, br, 1 H, NH); 7.15 (s, 1H, H 4 -thiazole); 7.02 (s, 1H, H5-thiazole); 3.79 (s, 2H, _CH2); 3.6 (q, 2H, _{CH2 CF3);} 3.1 (m, 1H, CHMe ₂ ); 1.11 (d, 6H, CHMe ₂ );

2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

1.1. 136-137 ° C 1 H-NMR (DMSO-d ₆ ) ppm: 12 (s, br, 1H, NH); 7.11 (s, 1H, H 4 -thiazole); 7.1 (d, 2H, Ph); 6.65 (d, 2H, Ph); 3.55 (s, 2H, _CH2); 3.1 (m, 1H, CHMe ₂ ); 2.82 (s, 6H, NMe ₂ ); 1.21 (d, 6H, CHMe ₂ );

2- [4- (acetylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide

1.1. 186-187 ° C 1 H-NMR (DMSO-d 6) ppm: 12.09 (s, br, 1H, NH); 9.9 (s, br, 1 H, NH); 7.6-7.2 (m, 4H, Ph); 7.15 (s, 1H, H 4 -thiazole); 3.62 (s, 2H, _CH2); 3.08 (m, 1H, CHMe ₂ ); 2- (s, 3H, CH ₃ ); 1.21 (d, 6H, CHMe ₂ );

tert-butyl 2 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] 2-oxoethyl} -1,3-thiazol-2-yl) amino] -2- oxoethylcarbamate;

tert-butyl 3 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -3 -oxopropylkarbamát; and tert-butyl 4 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] - 4-oxobutylcarbamate;

2- [4- (dimethylamino) phenyl] -N- (5-nitro-l, 3-thiazol-2-yl) acetamide; 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-nitro-1,3-thiazol-2-yl) acetamide; and N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide.

Example 5

Preparation of N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-methylpropanamide

To a solution of isobutyric acid (49 μΐ, 0.53 mmol) in CH ₂ C1 ₂ (1.5 ml) was added N-cyclohexylcarbodiimide, N'-methyl polystyrene (0.4 g, loading 2 mmol / g, 0.798 mmol ), N-hydroxybenzotriazole (0.072 g, 0.53 mol) and a solution of 2- (2-amino-, 3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide (0.075 g, 0.266 mmol) in CH ₂ Cl ₂ / DMF (0.4 mL / 0.6 mL). The reaction mixture is kept under stirring at room temperature for about 8 days.

PS-Trisamine (0.44 g, charge 3.62 mmol) / g, 1.596 mmol) was then added and stirring continued for 6 hours and then the mixture was filtered. The resin was washed with CH ₂ Cl ₂ (1 mL x 5), the organic layer was combined and evaporated to dryness to afford the title compound after trituration with diisopropyl ether.

Analogously starting from the corresponding carboxylic acids, the following compounds were prepared: N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) -acrylamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2-naftanamid; N- (4- (2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) benzamide; 2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl-acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) acetamide;

2,2,3,3,3-pentafluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2- yl) propanamide;

2-fluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide;

2-cyano-N- (4- {2 - [(5-isopropyl-L, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (4-methyl- 1-piperazinyl) acetamide; 2- (4-benzyl-piperazinyl) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol 2-yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1-piperidinyl) acetamide;

2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2 yl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1H-l, 2,3,4-tetrazol-1-yl) acetamide;

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -5-oxo-2-pyrrolidinecarboxamide ; N'r- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -malonamide,

N '1' - (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinamide;

3- (1H-benzimidazol-2-yl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) propanamide; and

-acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide; 2-Cyclopropyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl-2-pyrazinecarboxamide ; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-propylamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl-1,3 -oxazole-4-carboxylic acid amide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3-dimethylbutanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-methyl-2-butenamide ;

3-Cyclopentyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (3-thienyl) -acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) acetamide; 2,2,2-trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxo-ethyl) -l, 3-thiazol-2-yl) -3- (2-thienyl) propanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (4-pyridinylsulfanyl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) -1,3-thiazole-4-carboxamide;

2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-cyclopropyl-1,3-thiazol-2-yl) acetamide.

Example 6

Preparation of ethyl 2 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -2- oxoacetate

A solution of ethyloxalyl chloride (1.2 mL, 10.6 mmol) in CHCl ₃ was added dropwise under cooling to 0 ° C to a solution of 2- (2-amino-1,3-thiazol-4-yl) -N- ( 5-isopropyl-1,3-thiazol-2-yl) acetamide (2.5 g, 8.85 mmol). The reaction mixture was stirred for about 1 hour at 0 ° C and room temperature overnight, then washed with water, 5% citric acid, saturated sodium bicarbonate solution, brine, dried over sodium sulfate and evaporated to give the title compound. , which was used without further purification (1.2 g).

Analogously starting from the corresponding acid chloride, the following compounds were prepared and used as raw materials ethyl 3 - [(4- (2 - [(5-isopropyl-1,3-thiazol-2-yl) amino) -2- oxoethyl} -1,3-thiazol-2-yl) amino] -3-oxopropanoate and ethyl 4 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) amino] -4-oxobutanoate.

Example 7

Preparation of 2 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -2- oxoacetic acid

The crude material obtained in Example 6 (0.5 g; 1.31 mmol) was dissolved in 1,4-dioxane / methanol (10 mL / 5 mL) and treated with 1 N NaOH (1.5 mL, 1.5 mL). mmol) at about 48 hours. While cooling in an ice bath, 1 N HCl (1.5 mL) was added and the resulting mixture was filtered, washed with methanol and dried to give the title compound as a colorless solid (0.25 g, 54%).

1.1. Mp 214-215 ° C.

1 H-NMR (DMSO-d 6) ppm: 12.65 (s, br, 1H, NH); 12.1 (s, br, 1 H, NH); 7.15 (s, 1H, H 4 -thiazole); 7.1 (s, 1H, thiazole H5); 4.8 (s, 2H, _CH2); 3.1 (m, 1H, CHMe ₂ ); 1.21 (d, 6H, CHMe ₂ ).

The following compounds can be prepared analogously: N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) - 3-oxo-beta alanine

1.1. 186-188 ° C 1 H-NMR (DMSO-d ₆ ) ppm: 12.77 (s, br, 1H, COOH); 12.22 (s, br. 1H, NH); 12.05 (s, br, 1 H, NH); 7.25 (s, 1H, H 4 -thiazole); 6.98 (s, 1H, H5-thiazole); 3.8 (s, 2H, _CH2 COOH); 3.42 (s, 2H, _CH2); 3.2 (m, 1H, CHMe ₂ ); 1.22 (d, 6H, CHMe ₂ ); and

4 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -4-oxobutanoic acid .

Example 8

Preparation of 2- [2- (glycoloylamino) -1,3-thiazol-4-yl] -N- (5-iso-propyl-1,3-thiazol-2-yl) -acetamide

The crude material obtained in Example 6 (0.7 g, 1.8 mmol) was partially dissolved in a mixture of diethyl ether and tetrahydrofuran (65 mL / 30 mL) and treated with methanol (0.13 mL, 3.15 mmol) and LiBH ₄ (0.07 g, 3.15 mmol). The reaction mixture was stirred at 45 ° C for 20 minutes, tetrahydrofuran (20 mL) was added, and after 1 hour, additional methanol (0.03 mL) and LiBH ₄ (0.018 g) were added. Stirring is continued for 1 hour, the suspension is quenched with 1N HCl, diluted with water and extracted with CH ₂ Cl ₂ . The organic layer was washed with 1N HCl, brine, dried and evaporated. The residue is triturated with diisopropyl ether and then chromatographed on silica gel using CHCl 3: MeOH: 30% NH ₄ OH 97: 3: 0.3 as eluent to give the title compound as a colorless solid,

1.1. Mp 173-175 ° C

1 H-NMR (CDCl 3) ppm: 6.95 (s, 1H, H 4 -thiazole); 6.7 (s, 1H, H5-thiazole); 4.26 (s, 2H, _CH2 OH); 3.8 (s, 2H, _CH2); 3.1 (m, 1H, CHMe ₂ ); 1.21 (d, 6H, CHMe ₂ ).

The following compounds can be prepared analogously starting from the corresponding ester derivatives

3-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; and

4-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide.

Example 9

Preparation of 2- (dimethylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide

A mixture of 2-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide (0 5 g, 1.4 mmol), 2M dimethylamine in methanol (3.5 mL, 7 mmol) and potassium iodide (0.116 g, 0.7 mmol) were heated at reflux for 6 hours. After cooling, the solution is diluted with water, acidified with 1N HCl and extracted with diethyl ether to eliminate unreacted products. The aqueous solution was then basified with 1N NaOH and extracted with diethyl ether. The organic layer was dried over sodium sulfate and evaporated. The residue obtained is purified by chromatography on silica gel using CH ₂ Cl ₂ : MeOH 97: 3 and then 95: 5 as eluent. The title compound was obtained in 20% yield (0.1 g) as a light yellow solid.

1.1. 70-71 ° C 1 H-NMR (DMSO-d 6) ppm: 12.1 (s, br, 1H, NH); 11.8 (s, br, 1 H, NH); 7.17 (s, 1H, H 4 -thiazole); 6.95 (s, 1H, H5thiazole); 3.75 (s, 2H, CH ₂ NMe _2); 3.17 (s, 2H, _CH2); 3.1 (m, 1H, CHMe ₂ ); 2.12 (s, 6H, NMe ₂ ); 1.22 (d, 6H, CHMe ₂ ).

Example 10

Preparation of (2- (2 - {[2-dimethylamino) -2-oxoethyliamino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide

A mixture of 2- (2-amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide (0.6 g, 2.12 mmol), 2 -chloro-N, N-dimethylacetamide (0.27 mL, 1.96 mmol) and dry potassium carbonate (0.54 g, 3.92 mmol) in dry DMF (5 mL) was stirred at 60 ° C for 4 hours . The mixture was cooled, the solution was diluted with water and extracted with CHCl ₃ . The organic layer was washed with brine, dried and evaporated. The residue was purified by silica gel chromatography using CH ₂ Cl ₂ then CH ₂ Cl ₂ : MeOH as eluent. The title compound is obtained in 62% yield (0.5 g) as a colorless solid,

1.1. Mp 211-213 ° C.

1 H-NMR (DMSO-d 6) ppm: 7.02 (s, 1H, H 4 -thiazole); 6.75 (s, 1H, H5-thiazole); Δ (s, 2H, NHCH ₂ ); 3.43 (s, 2H, NHCOCH _2); 3.55 (s, 2H, _CH2); 3.1 (s, 3H, NMe); 2.98 (m, 1H, CHMe ₂ ); 2.82 (s, 3H, NMe); 1.2 (d, 6H, CHMe ₂ ).

The following compounds can be prepared analogously starting from the corresponding alkyl halide

2- {2- [2-amino-2-oxoethyl) amino] -l, 3-thiazol-4-yl} -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide

1.1. 172-174 ° C 1 H-NMR (DMSO-d 6) ppm: 7.6 (s, br, 1H, NHCO); 7.2 (s, br, 1 H, NH); 7.09 (s, 1H, H 4 -thiazole); 6.72 (s, 1H, H5-thiazole); 4.7 (s, 2H, NHCH ₂ ); 3.45 (s, 2H, NHCOCH _2); 2.95 (m, 1H, CHMe ₂ ); 1.2 (d, 6H, CHMe ₂ ); N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2 - {[2- (4-morpholinyl) ethyl] amino} -l, 3-thiazol-4-yl) -acetamide;

2- {2 - [(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;

2- [2- (l-adamantylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2 - {[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thiazol-4-yl ) acetamide; 2- (2 - {[3- (dimethylamino) -2-hydroxypropyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-methyl-l-piperazinyl) phenyl] acetamide;

N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-pyrrolidinyl) phenyl] acetamide;

N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4 - {[2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4 - {[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; 2- {4 - [(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- (4 - {[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide;

2- [4- (1-adamantylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- {4 - [(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide and 2- (4 - {[2- (dimethylamino) (2-oxoethyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide.

Example 11

Preparation of N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-methyl-1-piperarzinyl) ethyl] amino} -1,3-thiazole- 4-yl) acetamide

N- (5-Isopropyl-1,3-thiazol-2-yl) -2- (2 - {[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thiazol-4-yl ) acetamide (1 g, 2.45 mmol) and 40% formaldehyde in water (0.17 mL, 2.45 mmol) were mixed with CHCl ₃ (10 mL) and then treated with sodium triacetoxyborohydride (0.727 g, 3.43) mmol). The mixture was stirred at a temperature under nitrogen for 5 hours. The reaction mixture was quenched by the addition of aqueous saturated sodium bicarbonate solution and the product was extracted with CHCl ₃ . The organic layer was washed with brine, dried and evaporated. The title compound is obtained after chromatographic purification in 75% yield.

The following compounds can be prepared analogously:

2- {2 - [(2,3-dihydroxypropyl) (methyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide, N - (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl] amino} -1,3-thiazol-4-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide;

2- {4 - [(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide;

3 - [[2 - ({2- [4- (dimethylamino) phenyl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] propyl acetate;

2 - [[2 - ({2- [4- (dimethylamino) phenyl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] ethyl acetate;

2 - [[2 - ({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino) -1,3-thiazol-5-yl] (methyl) amino] ethyl acetate and

3 [[2 - ({2- [2- (acetylamino) -l, 3-thiazol-4-yl] acetyl} amino) -l _I, 3-thiazol-5-yl] (methyl) amino] propyl acetate.

Example 12

Preparation of N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxyacetamide

To a solution of 2-methoxyacetic acid (41 μΐ, 0.53 mmol) in CH ₂ C1 ₂ (1.5 ml), N-dicyclohexylcarbodiimide, N-methyl polystyrene (0.53 g, loading 2 mmol / g, 1.064 mmol) , pre-washing with CH ₂ C1 ₂ (5 mL x 3) was added 4-DMAP (0.032 g, 0.266 mmol) and a solution of 2- (4-aminophenyl) -N- (5-isopropyl-l, 3-thiazol-2 yl) acetamide (0.076 g, 0.266 mmol) in a mixture of CH ₂ C1 ₂ and DMF (0.4 ml / 0.6 ml). The reaction mixture is kept under stirring at room temperature for about 72 hours, the resin is filtered off, washed with CH ₂ Cl ₂ (10 ml x 3), the filtrate is combined, washed with water, 5% hydrochloric acid, water, saturated sodium bicarbonate and water, dried and evaporated.

Analogously, starting from the corresponding carboxylic acids, the following compounds can be prepared:

N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-thiophene-2-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-pyrazine-2-carboxamide;

N- (4-2- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-4-isoxazole-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4- iso xazolkarboxamid; (Dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;

4- (acetylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide;

4- (dimethylamino) -N- (4- {2 - _{[(5-isopropyl-1} 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -l, 3-benzodioxole-5-carboxamide;

4- (aminosulfonyl) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 2-chloro-2,2-difluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; 2-cyano-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide;

1-Acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide;

Ν '1' - (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide;

3,3,3-Trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenyl-acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenyl-acetamide;

2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide;

N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl) -2H-1,2] , 3,4-tetraaza-2-yljacetamid.

Example 13

Preparation of N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide

A mixture of 2.8 g (0.01 mol) of 2- (2-amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide, 4, 84 g (0.02 mol) of ethyl iodobutyrate and 2.76 g (0.02 mol) of potassium carbonate in 50 ml of absolute ethanol are stirred at reflux for 5 hours. The mixture was cooled and filtered and the salt washed with 20 ml of ethanol. The ethanol was removed under reduced pressure and the residue was dissolved in 100 mL of CH ₂ Cl ₂ . The solution was washed with 30 ml of water, dried and the solvent was evaporated. The residue was purified by silica gel chromatography using CH ₂ Cl ₂ : MeOH 95: 5 as eluent to give the title compound in 30% yield (1.05 g).

Example 14

Preparation of 1- (2,2-diethoxyethyl) cyclopropane

Diazomethane (6.17 g, 147 mmol) was added dropwise to 3.02 g (21 mmol) of 3-butenyl-diethyl acetal in 10 mL of dry ether with vigorous stirring at 0 ° C. Then, 70 mg (0.312 mmol) of palladium acetate in 50 ml of dry ether are added in one portion. Stirring is continued at 0 ° C until N ₂ evolution (10 min.) Occurs. The ether was distilled off to a reaction volume of 10 ml. The precipitate was filtered off on a glass filter and the filtrate was evaporated. The crude product (2.57 g) contained 97% of the title compound (GC) which was used without further purification.

Example 15

Preparation of 1- (2,2-Diethoxyethyl) cyclopropane 2-cyclopropylacetaldehyde (2.57 g, 16 mmol) was suspended in aqueous HCl (0.1 M, 120 mL) and stirred at room temperature for 30 hours where TLC indicated a complex converting the product to obtain a cloudy solution. The reaction mixture is then extracted with ether. The ether solution was washed with water, dried and the solvent was evaporated. The obtained residue was purified by silica gel chromatography using petroleum ether / ethyl acetate 95: 5 as eluent to give the title compound as an oil (1.07 g, 80%).

Example 16

Preparation of 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-amino-1,3-thiazol-2-yl) acetamide

A solution of 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-nitro-1,3-thiazol-2-yl) acetamide (1 g, 3.23 mmol) in ethanol (150 mL) was hydrogenated in the presence of 10% Pd / C (0.1 g, 10% w / w) at room temperature for 5 hours. The reaction mixture was filtered and evaporated. The residue was triturated with diisopropyl ether to give the title compound in 89% yield (0.8 g).

The following compound can be prepared analogously, starting from the corresponding nitro derivative:

2- [4- (dimethylamino) phenyl] -N- (5-amino-1,3-thiazol-2-yl) acetamide.

Example 17

Preparation of 3 - {[2- (2-acetylamino) -1,3-thiazol-4-yl] amino) -1,3-thiazol-5-yl] amino} propyl acetate

A solution of 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- (5-amino-1,3-thiazol-2-yl) -acetamide (0.5 g, 1.79 mmol),

Of 3-bromopropyl acetate (0.4 g, 2.15 mmol), 2,6-lutidine (0.25 mL, 2.15 mmol) in DMF (10 mL) was heated at 70 ° C for 72 hours. The reaction mixture was diluted with water, acidified with 0.5 N HCl and extracted with CH 2 Cl 2. The aqueous layer was adjusted to pH 7/8 with 0.5 N NaOH and extracted with CH ₂ Cl ₂ . The organic layer was washed with brine, dried and evaporated. The residue obtained is chromatographed on silica gel using CH ₂ Cl ₂ : MeOH 95: 5 as eluent to give the title compound in 45% yield.

The following compounds can be prepared analogously:

2 - {[2- ({2- [2- (acetylamino) -1,3-thiazol-4-yl] acetyl} amino) -1,3-thiazol-5-yl] amino} ethyl acetate;

2 - {[2- ({2- [4- (dimethylamino) phenyl] acetyl} amino-1,3-thiazol-5-yl] amino} ethyl acetate and 2 - {[2 - ({2- [4- ( dimethylamino) phenyl] acetyl} amino-l, 3-thiazol-5-yl] amino} propyl acetate.

Example 18

Preparation of 2- [2-) acetylamino) -1,3-thiazol-4-yl] -N- {5 - [(3-hydroxypropyl) (methyl) amino] -1,3-thiazol-2-yl} acetamide

3 - [[2 - ({2- [2- (Acetylamino) -1,3-thiazol-4-yl] acetyl} amino-1,3-thiazol-5-yl] (methyl) aminopropylacetate (0.5 g) (1.27 mmol) was dissolved in methanol (50 mL) and treated with 1N NaOH (1.4 mL, 1.4 mmol) at about 0 ° C for 24 h. The solvent was evaporated and the residue dissolved in the mixture. CH ₂ Cl ₂ and water The organic layer is chromatographed on silica gel using CH ₂ Cl ₂ 95: 5 as eluent to give the title compound in 40% yield.

The following compounds can be prepared analogously: 2- [2- (acetylamino) -1,3-thiazol-4-yl] -N- {5 - [(3-hydroxypropyl) amino] -1,3-thiazol-2-yl } -acetamide; 2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- {5 - [(2-hydroxyethyl) (methyl) amino] -l, 3-thiazol-2-yl} acetamide; 2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- {5 - [(2-hydroxyethyl) amino] 3-thiazol-2-yl} acetamide; and 2- [4- (dimethylamino) phenyl] -N- {5 - [(2-hydroxyethyl) amino] -1,3-thiazol-2-yl} acetamide; 2- [4- (dimethylamino) phenyl] -N- {5 - [(2-hydroxyethyl) (methyl) amino] -l, 3-thiazol-2-yljacetamid; 2- [4- (dimethylamino) phenyl] -N- {5 - [(3-hydroxypropyl) (methyl) amino] -l, 3-thiazol-2-yl} acetamide; and 2- [4- (dimethylamino) phenyl] -N- {5 - [(3-hydroxypropyl) amino] -1,3-thiazol-2-yl} acetamide.

Obviously, there are many modifications and variations based on these techniques. It is to be understood, therefore, that the scope of the appended claims may be practiced otherwise than as specifically described herein.

PATENT CLAIMS

Claims (27)

Use of a compound of formula (I) or (II) for the manufacture of a medicament for the treatment of cell proliferative diseases related to altered cell-dependent kinase activity by administering to a mammal in need thereof an effective amount of a compound of formula (I) or (II). (I) where L is a phenyl or 5 to 6-membered aromatic heterocycle, with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R is (i) a C ₃ -C ₆ cycloalkyl group optionally substituted by a straight or branched C 1 -C ₆ alkyl group; or (ii) _Ci-C6 alkyl, straight or branched chain alkyl or arylalkyl group which is optionally substituted by one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, C ₆ straight or branched chain alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, alkyl-C _{3 C6} cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, aralkylcarbonylamino, arylaminosulfonyl, arylalkylaminosulfonylu, arylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl , arylalk ylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-arylpiperazino, N-arylalkylpiperazino, piperidino and azabicyclo [3.2.2] nonane; R ¹ is H or C _r C ₄ alkyl, straight or branched chain substituted with one or more hydroxy, alkoxy, amino, alkylamino or dialkylamino; R ² and R ^3, which may be the same or different, are hydrogen, cycloalkyl, linear or branched C _r C ₆ alkyl group or an aryl group which may be optionally substituted as described for R; or R ² and R ³ together with the nitrogen atom to which they are attached form 4-morpholinyl, 1-piperazinyl, N-alkylpiperazinyl, N-arylpiperazinyl, N-arylalkylpiperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring; R ⁴ is carboxy, perfluorinated alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl group, 2-oxopyrolidinyová, piperidinyl or C _r C ₆ alkyl group, a linear or branched, or an aryl group which is optionally substituted as described for R; or a pharmaceutically acceptable salt thereof, provided that the compound is not 2- (4-aminophenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide, 2- (2-Amino-1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide, 2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide, N- (5-benzyl-1,3-thiazol-2-yl) -2 - [4- (dimethylamino) phenyl] acetamide, N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- (dimethylaminophenyl) acetamide or 2-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide. The use of claim 1, wherein the cell proliferative disease is selected from the group consisting of cancer, Alzheimer's disease, viral infections, autoimmune diseases, or neurodegenerative diseases. The use according to claim 2, wherein the cancer is selected from the group consisting of carcinoma, squamous cell carcinoma, hematopoietic tumors of the myeloid or lymphoid lineage, tumors of mesenchymal origin, tumors of the central or peripheral nervous system, melanoma, seminoma, teratocarcinoma, osteocarcinoma, osteocarcinoma, osteocarcinoma, keratoctantoma, thyroid follicular cancer, and Kaposi's sarcoma. The use according to claim 1, wherein the cell proliferative disease is selected from the group consisting of benign prostatic hyperplasia, familial adenomatous polyposis, neuroflbromatosis, psoriasis, atherosclerosis-related smooth muscle cell proliferation, pulmonary fibrosis, arthritic glomerulonephritis, and postoperative stenosis and postoperative stenosis. The use of claim 1, wherein the treatment provides inhibition of tumor angiogenesis and metastasis. The use of claim 1, wherein the treatment provides cell cycle inhibition and / or cdk / cyclin dependent inhibition. The use of claim 1, wherein the mammal is further subjected to a radiation therapy or chemotherapy regimen in combination with at least one cytostatic or cytotoxic agent if desired. Use according to claim 1, wherein the compound is represented by the general formula (I). Use according to claim 1, wherein the compound is represented by the general formula (II). The use of claim 1, wherein L is selected from the group consisting of phenyl, thiazole, imidazole, oxazole, pyrazole, isoxazole, thiophene, pyridine and pyrimidine; ^R is (i) C ₃ -C ₆ cycloalkyl, optionally substituted alkyl, or (ii) a straight or branched C _r C ₄ alkyl or aralkyl, optionally substituted as above, R ¹ is hydrogen or a Cu- A C 4 alkyl group optionally substituted by a hydroxy or amino group; or a pharmaceutically acceptable salt thereof. The use of claim 1, wherein the compound is selected from the group consisting of N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} - 1,3-thiazol-2-yl) -acrylamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2-methylpropanamide; 2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-naphthamide; (5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -benzamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl-acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) acetamide; 2.2.3.3.3-Pentafluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide, 2 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -2- oxoacetic acid; 2-fluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l) 3-thiazol-2-yl) -acetamide; 2-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; 2-cyano-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -3-oxo-beta-alanine ; N'1 '- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malonamide; 4 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-oxobutyric acid ; 2- [2- (glycoloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 3-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; 3-amino-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; 2-Amino-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide; 4-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide; 4-amino-N- (4- (2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) butanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (4-methyl- 1-piperazinyl] acetamide; 2- (4-benzyl-1-piperazinyl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1-piperidinyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [2- (2-oxo-l-pyrrolidinyl) -l, 3-thiazol-4-yl] acetamide; 2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2 yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1H-1) 2,3,4-tetraazol-1-yl] acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2-pyrrolidinecarboxamide; - {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinamide; 3- (1H-benzimidazol-2-yl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) propanamide; 1-Acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide ; 2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 4-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2-methoxy-acetamide; 3,3.3-trifluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; 2- (dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2 - {[2- (4-methyl-l-piperazinyl) ethyl] amino} -l, 3-thiazol-4-yl ) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2- {methyl- [2- (4-methyl-1-piperazinyl) ethyl] amino) -1,3-thiazol-4- yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2 - {[2- (4-morpholinyl) ethyl] amino} -l, 3-thiazol-4-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl)] amino} -l, 3-thiazol-4-yl) acetamide ; 2- {2 - [(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- {2 - [(2,3-dihydroxypropyl) (methyl) amino] -l, 3-thiazol-4-yl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- (2 - {[3- (dimethylamino) -2-hydroxypropyl] amino} -1,3-thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- {2 - [(2-amino-2-oxoethyl) amino] -l, 3-thiazol-4-yl} -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide; 2- (2 - {[2- (dimethylamino) -2-oxoethyl] amino} -l, 3-thiazol-4-yl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- [2- (adamantylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (4-methyl-1-piperazinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (l-pyrrolidinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4 - {[2- (4-methyl-l-piperazinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4- {methyl [2- (4-methyl-l-piperazinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4 - {[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; 2- {4 - [(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- {4 - [(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide; 2- (4 - {[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- [4- (1-adamantylamino) phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- {4 - [(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- (4 - {[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide; 2- [4- (acetylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-thiophene-2-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-pyrazine-2-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-isoxazole-4-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isoxazolecarboxamide; (Dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 4- (acetylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 4- (dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -l, 3-benzodioxole-5-carboxamide; 4- (aminosulfonyl) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 2-chloro-2,2-difluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; 2-cyano-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; 1-Acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide; N'ľ- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-acetamide; 3,3,3-trifluoro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenyl-acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenyl-acetamide; 2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (l-pyrrolidinyl) -2H-l, 2 , 3,4-tetraaza-2-yljacetamidu; 2-Cyclopropyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -5-methyl-2-pyrazinecarboxamide ; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-propynamidu; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -5-methyl-3 oxazole-4-carboxamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3-dimethylbutanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -3-methyl-2-buténaniidu ; 3-Cyclopentyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-thienyl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) acetamide; 2,2,2-trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3- (2-thienyl) propanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] oxoethyl} -1,3-thiazol-2yl) - (4-pyridinylsulfanyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (3-pyridyl) -l, 3-thiazole-4-carboxamide; 2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- (5-cyclopropyl-l, 3-thiazol-2-yl) acetamide; N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide and pharmaceutically acceptable salts thereof. The use of claim 1, wherein the mammal is a human. A 2-amino-1,3-thiazole derivative represented by the general formula (I) or (II) wherein: L is a phenyl group or a 5 to 6-membered aromatic heterocycle, with one or more heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; R is (i) a C ₃ -C ₆ cycloalkyl group optionally substituted by a straight or branched C 1 -C ₆ alkyl group; or (ii) a C1-C (5 straight or branched chain alkyl or arylalkyl group optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, carboxy, hydroxy, nitro, alkylthio, alkoxy, C] _C6 alkyl, straight or branched alkyl, arylthio, aryloxy, amino, alkylamino, dialkylamino, arylamino, arylalkylamino, hydroxyaminocarbonyl, alkoxyaminocarbonyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl, C ₃ -C ₆ cycloalkyl, alkyl C ₃ -C ₆ cycloalkyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkylsulfonyl, arylsulfonyl, arylalkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl, alkylcarbonylamino, arylalkylaminosulfonylu, arylcarbonylamino, aralkylcarbonylamino, alkylsulfonylamino, arylsulfonylamino, arylalkylsulfonylamino, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, dialkylaminocarbonyl, aryls nocarbonyl, arylalkylaminocarbonyl, pyrrolidino, morpholino, piperazino, N-alkylpiperazino, N-arylpiperazino, N-arylalkylpiperazino, piperidino and azabicyclo [3.2.2] nonane substituents; R ¹ is a hydrogen atom or a straight or branched C 1 -C ₄ alkyl group optionally substituted by one or more hydroxy, alkoxy, amino, alkylamino or dialkylamino groups; R ² and R ³ , which may be the same or different, are a hydrogen atom, a cycloalkyl group, a straight or branched C 1 -C ₆ alkyl group or an aryl group, which are optionally substituted as described for R 2; or R ² and R ³ together with the nitrogen atom to which they are attached form 4-morpholinyl, 1-piperazinyl, N-alkylpiperazinyl, N-arylpiperazinyl, N-arylalkylpiperazinyl, piperidinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, imidazolyl or 3-azabicyclo [3.2.2] nonyl ring; R ⁴ is carboxy, perfluorinated alkyl, C ₂ -C ₄ alkenyl, C ₂ -C ₄ alkynyl group, 2-oxopyrolidinyová, piperidinyl or C _r C ₆ alkyl group, a linear or branched, or an aryl group which is optionally substituted as described for R; or a pharmaceutically acceptable salt thereof, provided that the compound is not 2- (4-aminophenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide, 2- (2-amino-1,3 -thiazol-4-yl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- [4- (dimethylamino) phenyl] -N- (5-isobutyl-1,3- thiazol-2-yl) acetamide, N- (5-benzyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide, N- (5-isopropyl-1,3-thiazole) -2-yl) -2- (4- (dimethylaminophenyl) acetamide or 2-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl) } -l, 3-thiazol-2-yl) acetamide. A 2-amino-1,3-thiazole derivative according to claim 13, which is represented by the general formula (1). A 2-amino-1,3-thiazole derivative according to claim 13, which is represented by the general formula (II). The 2-amino-1,3-thiazole derivative according to claim 13, wherein L is selected from the group consisting of phenyl, thiazole, imidazole, oxazole, pyrazole, isoxazole, thiophene, pyridine and pyrimidine; R is (i) C ₃ -C ₆ cycloalkyl, optionally substituted alkyl, or (ii) a straight or branched C _r C ₄ alkyl or aralkyl, optionally substituted as described above, R ¹ is H or C _r C ₄ alkyl optionally substituted by hydroxy or amino; or a pharmaceutically acceptable salt thereof. The 2-amino-1,3-thiazole derivative according to claim 13, which is selected from the group consisting of N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] - 2-oxo-ethyl} -l, 3-thiazol-2-yl) -acrylamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2-methylpropanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-naphthamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -benzamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2-phenyl-acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) acetamide; 2,2,3,3,3-pentafluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol 2-yl) propanamide; 2 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) amino] -2-oxoacetic acid ; 2-fluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} _-l) 3-thiazol-2-yl) -acetamide; 2-chloro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide; 2-cyano-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-oxo-beta-alanine ; 1 '- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) malonamide; 4 - [(4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-oxobutyric acid ; 2- [2- (glycoloylamino) -1,3-thiazol-4-yl] -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 3-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; 3-amino-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; 2-Amino-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -acetamide; 4-hydroxy-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide; 4-amino-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) butanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (4-methyl- piperazinyl) acetamide; 2- (4-Benzyl-1-piperazinyl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1-piperidinyl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- [2- (2-oxo-1-pyrrolidinyl) -1,3-thiazol-4-yl] acetamide; 2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2 yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (1H-1) 2,3,4-tetraazol-1-yl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole-2-pyrrolidinecarboxamide; NT- (4- { 2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) succinamide; 3- (1H-benzimidazol-2-yl) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazole- 2-yl) propanamide; 1-Acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -4-piperidinecarboxamide ; 2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 4-chloro-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) butanamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2-methoxy-acetamide; 3,3,3-Trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) propanamide; 2- (dimethylamino) -N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (2 - {[2- (4-methyl-1-piperazinyl) ethyl] amino} -1,3-thiazol-4-yl ) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2- {methyl [2- (4-methyl-l-piperazinyl) ethyl] amino} -l, 3-thiazol-4- yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2 - {[2- (4-morpholinyl) ethyl] amino} -l, 3-thiazol-4-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (2- {methyl [2- (4-morpholinyl) ethyl)] amino} -l, 3-thiazol-4-yl) acetamide ; 2- {2 - [(2,3-dihydroxypropyl) amino] -1,3-thiazol-4-yl} -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- {2 - [(2,3-dihydroxypropyl) (methyl) amino] -l, 3-thiazol-4-yl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- (2 - {[3- (dimethylamino) -2-hydroxypropyl] amino} -l, 3-thiazol-4-yl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- {2 - [(2-amino-2-oxoethyl) amino] -l, 3-thiazol-4-yl} -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide; 2- (2 - {[2- (dimethylamino) -2-oxoethyl] amino} -l, 3-thiazol-4-yl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- [2- (adamantylamino) -l, 3-thiazol-4-yl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- [4- (dimethylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-methyl-l-piperazinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- [4- (4-morpholinyl) phenyl] acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- [4- (1-pyrrolidinyl) phenyl] acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4 - {[2- (4-methyl-l-piperazinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-1,3-thiazol-2-yl) -2- (4- {methyl [2- (4-methyl-1-piperazinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4 - {[2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; N- (5-isopropyl-l, 3-thiazol-2-yl) -2- (4- {methyl [2- (4-morpholinyl) ethyl] amino} phenyl) acetamide; 2- {4 - [(2,3-dihydroxypropyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- {4 - [(2,3-dihydroxypropyl) (methyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide; 2- (4 - {[3- (dimethylamino) -2-hydroxypropyl] amino} phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- [4- (1-adamantylamino) phenyl) -N- (5-isopropyl-1,3-thiazol-2-yl) acetamide; 2- {4 - [(2-amino-2-oxoethyl) amino] phenyl} -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; 2- (4 - {[2- (dimethylamino) -2-oxoethyl] amino} phenyl) -N- (5-isopropyl-l, 3-thiazol-2-yl) -acetamide; 2- [4- (acetylamino) phenyl] -N- (5-isopropyl-l, 3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) nicotinamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-thiophene-2-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-pyrazine-2-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -5-methyl-isoxazole-4-carboxamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -3,5-dimethyl-4-isoxazolecarboxamide; (Dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 4- (acetylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 4- (dimethylamino) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -1,3-benzodioxole-5-carboxamide; 4- (aminosulfonyl) -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) benzamide; 2-chloro-2,2-difluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; 2-cyano-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; 1-Acetyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -4-piperidinecarboxamide; N '- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) succinamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-acetamide; 3,3,3-trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) propanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-phenylacetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2-methoxy-2-phenyl-acetamide; 2- [4- (dimethylamino) phenyl] -N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-pyridinyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- (3-thienyl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} phenyl) -2- [5- (1-pyrrolidinyl) -2H-1,2 , 3,4-tetraaza-2-yl] acetamide; 2-Cyclopropyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -5-methyl-2-pyrazinecarboxamide ; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-propynamidu; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -5-methyl-3 oxazole-4-carboxamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3,3-dimethylbutanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -3-methyl-2-butenamide ; 3-cyclopentyl-N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) propanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-thienyl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -2- (3-pyridyl) acetamide; 2,2,2-trifluoro-N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) acetamide; N- (4- {2 - [(5-isopropyl-l, 3-thiazol-2-yl) amino] -2-oxoethyl} -l, 3-thiazol-2-yl) -3- (2-thienyl) propanamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] oxoethyl} -1,3-thiazol-2yl) - (4-pyridinylsulfanyl) acetamide; N- (4- {2 - [(5-isopropyl-1,3-thiazol-2-yl) amino] -2-oxoethyl} -1,3-thiazol-2-yl) -2- (3-pyridinyl) -1,3-thiazole-4-carboxamide; 2- [2- (acetylamino) -l, 3-thiazol-4-yl] -N- (5-cyclopropyl-l, 3-thiazol-2-yl) acetamide; N- (5-cyclopropyl-1,3-thiazol-2-yl) -2- [4- (dimethylamino) phenyl] acetamide and pharmaceutically acceptable salts thereof. A process for the preparation of a 2-aminol, 3-thiazole derivative according to claim 13 or a pharmaceutically acceptable salt thereof, comprising reacting a compound of formula (III): (III), and compounds of formula (IV): (IV), wherein R, L, R ¹ , R ² and R ³ are as defined in claim 13 a Z is hydroxy or a suitable leaving group, to give a compound of formula (I) wherein R, L, R ¹ , R ² and R ³ are as defined in claim 13. A process for the preparation of a 2-amino-1,3-thiazole derivative according to claim 13, or a pharmaceutically acceptable salt thereof, comprising: reaction of a compound of formula (I): (I) (V), with a compound of formula (V): R ₄ -COX where R, R ¹ , L and R ⁴ are as defined in claim 13 a X is hydroxy or a suitable leaving group, to form the 2-amino-1,3-thiazole derivative represented by the general formula (II), wherein R, L, R ¹ and R ⁴ are as defined in claim 13. A process for the preparation of a 2-amino-1,3-thiazole derivative according to claim 13 or a pharmaceutically acceptable salt thereof, comprising reacting a 2-amino-1,3-thiazole derivative of formula (I) wherein both or at least one of R ² and R ³ is hydrogen, with a compound of formula (VI): R'-Y (VI), wherein R 'has the meanings of R ² or R ³ but other than hydrogen and Y is a suitable leaving group, to form a 2-aminol, 3-thiazole derivative of the general formula (I) wherein both or at least one of R ₂ and R ₃ is other than hydrogen; and optionally the 2-amino-1,3-thiazole derivative represented by the general formula (I) or (II) is transformed into another 2-amino-1,3-thiazole derivative represented by the general formula (I) or (II) and / or its salt. 21. A pharmaceutical composition comprising the 2-amino-1,3-thiazole derivative according to claim 13 and at least one pharmaceutically acceptable carrier and / or diluent. The use of any one of claims 1 to 10, wherein R is unsubstituted alkyl, cycloalkyl or arylalkyl. The use according to any one of claims 1 to 10, wherein R is isopropyl or cyclopropyl. The use of claims 22 or 23, wherein R is isopropyl. The 2-amino-1,3-thiazole derivative according to any one of claims 13 to 16, wherein R is unsubstituted alkyl, cycloalkyl or aralkyl. A 2-amino-1,3-thiazole derivative according to any one of claims 13 to 16, wherein R is unsubstituted alkyl, cycloalkyl or aralkyl. A 2-amino-1,3-thiazole derivative according to claim 25 or 26, wherein R is isopropyl.